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The Ser/Thr Kinase MAP4K4 Controls Pro-Metastatic Cell Functions

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The Ser/Thr Kinase MAP4K4 Controls Pro-Metastatic Cell Functions ooggeenneessii iinn ss && rrcc aa MM CC uu tt ff aa Journal ofJournal of oo gg ll ee aa nn nn ee rr ss uu ii Tripolitsioti D et al., J Carcinog Mutagen 2017, 8:1 ss oo JJ ISSN: 2157-2518 CarCarcinogenesiscinogenesis & Mutagenesis DOI: 10.4172/2157-2518.1000284 Review Article Open Access The Ser/Thr Kinase MAP4K4 Controls Pro-Metastatic Cell Functions Dimitra Tripolitsioti1, Michael A Grotzer1,2 and Martin Baumgartner1* 1Department of Oncology, Children’s Research Center, University Children's Hospital Zürich, August-Forel Strasse 1, CH-8008 Zürich, Switzerland 2Department of Oncology, University Children’s Hospital Zürich, Steinwiesstrasse 75, CH-8032 Zürich, Switzerland *Corresponding author: Martin Baumgartner, Department of Oncology, University Children's Hospital Zürich, Children’s Research Center, August-Forel Strasse 1, CH-8008 Zürich, Switzerland, Tel: +41 44 634 88 20; Fax: +41 44 634 88 59; E-mail: [email protected] Received date: December 20, 2016; Accepted date: January 31, 2017; Published date: February 03, 2017 Copyright: © 2017 Tripolitsioti D, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Abstract The search for novel targeted therapies for major human conditions such as diabetes, cardiovascular diseases and cancer is a slow and costly process. Progress is often hampered by poor drug efficaciousness in the patients, low selectivity/specificity of the compounds and cellular evasion mechanism that are rather common in anti-cancer therapies. This is particularly true also for compounds inhibiting kinases, which in theory are optimal targets thanks to their druggable enzymatic activity. Novel targeting strategies are needed to reduce side effects and treatment failure caused by non-specific drug function and target resistance, respectively. An ideal compound will repress the relevant kinase effector function, while leaving kinase functions that are not disease-relevant unaltered. To achieve function-specific inhibition, the molecular mechanism of the drug target that governs the pathological process, must be identified. The Ser/Thr kinase MAP4K4 is implicated in inflammatory and metabolic disorders and cancer progression. In this review, we describe the molecular effector functions of MAP4K4 that exert those activities and how they have been identified and characterized both in invertebrate organisms and mammals. We discuss how the modulation of the cellular cytoskeleton by MAP4K4 may be connected to pathological conditions such as aberrant angiogenesis and cancer metastasis, and we describe the molecular mechanisms that are so far known to be mechanistically involved in these processes. Keywords: MAP4K4; Cytoskeleton; Cancer metastasis; Cancer only a few interactors have so far been described, highlighting the still progression incomplete understanding we currently have of how MAP4K4 exerts its functions. Most of the so far identified MAP4K4 interactors are Introduction functionally associated with the modulation of the actin and microtubule cytoskeletons. It is thus tempting to speculate that MAP4K4 (Mitogen activated protein kinase kinase kinase kinase 4, MAP4K4 modulates cell behavior via targeting the underlying also known as Hepatocyte progenitor kinase-like/germinal center cytoskeleton dynamics. In this review, we will particularly focus on the kinase-like kinase (HGK) and Nck-interacting kinase (NIK)) is a role of MAP4K4 in cancer and cancer progression and discuss how serine/threonine protein kinase and member of the human STE20 MAP4K4-controlled cytoskeleton dynamics could initiate and sustain family kinases; it was first identified as a kinase interactor of the the complex morphodynamic processes associated with cancer adaptor protein Nck in mice [1] and short time later the human initiation and progression. orthologue was cloned as well [2]. The MAP4K4 gene is located on chromosome 2 at position q11.2 and encodes from 33 exons a protein Signaling Through MAP4K4 containing 1288 amino acids. Structurally, MAP4K4 contains an N- terminal kinase domain, a coiled-coil domain, a C-terminal Since its discovery in the late nineties, only relatively few details on hydrophobic leucine-rich citron homology domain (CNH) and two the regulation of MAP4K4 activity and its substrates could be revealed. putative caspase cleavage sites [3,4]. An interdomain connecting the This is all the more surprising, considering the wealth of its kinase and the CNH domain is involved in protein-protein interactions implications in development, metabolic disorders and cancer. but is structurally and functionally only poorly understood. Alternative Convincing evidence in different mammalian and fly cell systems splicing results in five isoforms that display differences in interdomain revealed MAP4K4 functions closely associated with the tumor necrosis composition, while kinase and CNH domain are 100% homologous. factor alpha (TNFα)-induced c-jun N-terminal kinase (JNK) signaling MAP4K4 is well conserved and orthologues are found across species. pathway [1,2,5,6]. TNFα-induced JNK activation by MAP4K4 involves Genetic interference and gene expression analyses have implicated signal transmission through the kinases TAK1, MKK4 and MKK7 [2]. MAP4K4 activity in a plethora of cellular functions relevant for Interestingly, MAP4K4 not only mediates TNF-α signaling but also physiological and pathophysiological processes, including organ promotes TNFα expression [2], while TNFα can also cause the specific development, systemic inflammation, metabolic disorders and cancer. increase in MAP4K4 expression via the transcription factors c-Jun and ATF2 [7,8]. On the one hand, this positive feed-back regulation of The astounding bandwidth of these functions, which are further TNFα signaling through MAP4K4 is likely involved in physiological detailed below, indicates the interaction of MAP4K4 with a range of cell functions during development and for tissue homeostasis. On the structurally and functionally different effectors. Surprisingly however, J Carcinog Mutagen, an open access journal Volume 8 • Issue 1 • 1000284 ISSN:2157-2518 Citation: Tripolitsioti D, Grotzer MA, Baumgartner M (2017) The Ser/Thr Kinase MAP4K4 Controls Pro-Metastatic Cell Functions. J Carcinog Mutagen 8: 284. doi:10.4172/2157-2518.1000284 Page 2 of 8 other hand, aberrant TNFα signaling through MAP4K4 was also linked to pathophysiological processes using genetic ablation and pharmacological inhibition approaches. These processes include insulin sensitivity [8], systemic inflammation [9], pathogen-dependent oncogenic progression [10,11] and vascular inflammation and atherosclerosis [12]. In addition to the TNFα-receptor, growth factors (GF) such as PDGF or EGF activate MAP4K4 through receptor tyrosine kinases (RTKs) [2] and trigger the phosphorylation and activation of the MAP4K4 substrates sodium- proton exchanger [1] (NHE1) [13], ezrin, radixin, moesin (ERM) family proteins [14] and actin-related protein [2] (Arp2) [15]. Genetic studies in C. elegans identified an interaction between the worm ortholog of MAP4K4–MIG-15–and integrin/PAT3 [16]. Whether integrin receptor engagement could activate MAP4K4 signaling analogous to the TNFα receptor or the RTKs described above is currently not known. However, compelling evidence indicates that MAP4K4 decreases surface availability of active integrins [17], for example by inactivating integrins via moesin phosphorylation, which concomitantly competes with talin for integrin binding [18], or by Figure 1: Overview of the major MAP4K4 signaling pathways. accelerating their endosomal trafficking [19]. Still in the context of integrin signaling, MAP4K4 was found to be phosphorylated by the focal adhesion kinase Pyk2 [20], which is From Insulin Resistance to Cell Motility: The Panoply regulated by intracellular calcium levels and activated by G-protein- of MAP4K4 Control of Physiological Processes coupled receptors [21]. Although not directly activated by transforming growth factor ß/ Glucose up-take and insulin function bone morphogenic protein (TGFß/BMP), MAP4K4 as well as the The pathological failure of cells to respond to insulin with glucose closely-related TNIK and MINK promote inhibitory phosphorylation up-take and metabolization is referred to as insulin resistance. It causes of Thr312 in the TGFß/BMP effector R-Smads1/2/3/5/8 [22]. blood glucose levels to raise above the normal range, is associated with Somewhat counterintuitively, MAP4K4 along with its relatives obesity, hypertension and cardiovascular diseases and eventually MAP4K1-6, were recently also found to phosphorylate and activate the results in type 2 diabetes [25,26]. Causative mechanisms for insulin kinase Large Tumor Suppressor 1/2 (LATS1/2) under conditions of resistance include impaired insulin receptor (IR) signaling and the serum starvation [23], which inactivates Yes-associated protein 1 concomitantly deficient ability to restrict hepatic glucose output, as (YAP1) in the evolutionary conserved Hippo pathway. Hippo pathway well as reduced uptake of glucose into muscle and adipose tissue activation and phosphorylation-dependent cytosolic retention of the through the glucose transporter GLUT4. An siRNA screen identified YAP transcriptional regulator is tumor suppressive, as it prevents pro- MAP4K4 as a negative regulator of GLUT4 control of glucose proliferative
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